Nu-(2-hydroxyethyl)-1, 2-bis(4-methoxyphenyl) ethylamine



Patented May 9, 195

N (Z-HYDROXYETHYL) -1,2-BIS (4- METHOXYPHENYL) ETHYLAMINE Louis H. Goodson, Kansas City, Mo., and Robert B. Mofiett, Kalamazoo, Mich, assignors to George A. Breon & Company, Kansas City, Mo., a corporation of Missouri N0 Drawing. Original application August 22,

1946, Serial No. 692,378. Divided and this application November 2, 1948, Serial No. 58,016

1 Claim. 1

This invention relates to therapeutic compositions and more particularly to analgesics.

Among the several objects of the invention may be noted the provision of new analgesic compositions; the provision of new analgesic compositions that are readily soluble in available solvents to form stable solutions; the provision of new analgesic compositions that are readily administered; the provision of analgesic compositions that are relatively non-toxic and cause no serious complications or side reactions following administration; the provision of methods for manufacturing analgesic compositions of the class indicated that are characterized by their high yields, inexpensive and readily procurable reaction materials, and the facility with which they may be carried out; and the provision of new secondary amines having analgesic properties. Other objects will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the ingreclients and combinations of ingredients, the proportions thereof, steps and sequence of steps, and features of composition and synthesis, analysis, or metathesis, which will be exemplified in the products and processes hereinafter described, and the scope of the application of which will be indicated in the following claims.

According to the present invention analgesic compositions having desirable properties are provided. They are easily soluble in desired proportions in water, and are capable of being stored for long periods of time without being chemically, therapeutically or physically affected. The amount administered for eifective analgesic action is substantially lower than that which is toxic. It has been found that analgesic compositions of the class described can be readily made in the form of powders, tablets, capsules, and ampules, to be used for any desired type of administration.

The analgesic compositions of the present invention have as an essential ingredient thereof, one or more compounds of the following formula:

where R is an alkyl alkenyl or B-hydroxyethyl radical and R, R" and R' are the same or different and are hydrogen, hydroxy, alkoxy or alkylenedioxy radicals.

The analgesic compositions of the present inention were tested for their therapeutic efficacy by the following method. Adult male albino white mice were injected subcutaneously under the skin of the back just anterior to the tail. After a certain time interval, e. g. 10 minutes, a mouse so treated was placed on a hot circular plate surrounded by a hollow transparent cylinder. The time required for the mouse to show the effect of the heat, called hereinafter the reaction time, was determined by noting how long the mouses hind feet would remain immobile or be normally active. The mouse would then be removed from the heated plateand after another time interval, e. g. 10 minutes, would be retested for reaction time. This procedure was repeated until the reaction time was less than a control time. This control time for each mouse was measured by determining how long the mouse, before injection, would remain on the heated plate without the abnormal movement of the hind feet referred to above.

The reaction time for the analgesic compositions described subsequently was found to be substantially greater than the control time, and no harmful after effects of any type were noted.

A sufficient number of normal mice were used in all tests to be sure that susceptibility due to age variations and other physical conditions were minimized. The fatal doses of the various compositions of the class described were also determined and found to be at concentrations substantially greater than the desired concentrations for effective analgesic action.

The amine ingredients of the analgesic compositions may be prepared by several general methods such as, for example, by the reaction of an appropriate benzyl phenyl ketone with an alkyl, alkanol or alkylene amine and formic acid and hydrolysis of the resulting amide, to give the desired N-substituted 1,2-diarylethylamine.

Also these compounds may be prepared by treating an appropriate aromatic aldehyde with a primary amine, treating the resulting Schiifs base with a substituted or unsubstituted benzyl magnesium halide and then isolating the desired N -substituted 1,2-diarylethylamine.

Furthermore these compounds may be prepared by the direct alkylation of the appropriatel,2-diarylethylamine with agents such as direaction product.

A secondary amine of this type also may be prepared by the hydrogenationof ajketoneofthe amine in 71 ml. of dry dioxane was added to benzyl magnesium chloride (prepared from 13.6 g. of magnesium, 65 ml. of. benzyl chloride and 200 m1. of dry ether) The mixture became very thick and 109 ml, of'dry benzene were added to facilitate stirring. After decomposing the reaction mixture with ice and hydrochloric acid, the layers were separated and the aqueous layer was concentrated in vacuo. The hydrochloride crystallized. out and was recrystallized from methanol.

. The MJP. was 201-202 C. This product was type ArylCH2CO-Aryl" in the presence of a.

catalyst and a primary amine.

While there are other methods of preparing the amines used in making the analgesic com positions of the present intention. the. methods,

already outlined are preferred. The following examples illustrate the present invention. They are exemplary only.

EX MPLE ii-m mm-c-m m' w-4- p m z qmme hydrochlor I CHf-H-NHCHa-HCI 3.;-methoxyeehydroxybenzalmethylamine was preparedb'y heatinga. suspension of 76.07 g. of vanillinx-andlBfi g. ofzmethylamine in 300ml. of benzene and removing the water iormedinthe reaction .hy refluxing the benzene with a continu- 0.11s; water. separating. device. The product was crystallized first: frombenzene. and then: from dioxane giving white crystals. M. P. 131-1345.? C.

A solution of 33.8 g. of; this .product'in 100 ml. of:hot;dry dioxane. was added to a. stirredsolution. of. benzyll magnesium chloride (prepared iron-119.5%. .of;magnesium; 92 ml. .of :benzyl chloride, .and:30.0..ml. ofjdlfy ether). After'refluxing for-some time, the mixture set to a solid and the lumpsgwerezthen broken up and added :to ice and hydrochloric. acid; On standinga crystalline precipitate. separated. which was recrystallized frompmetlianol giving white crystals of the hydrochloride which melts at 178-180": C. and on con- 1 timIedJbeating. of; the sample. it resolidified and melted again at 227-230?- 'C. Thisjproduct was dissolved; intriple-distilled water to make an analgesic composition of the desired concentration, ,sui,table for administration.

Nemethyl-la 3 -hyd1roxyphenyl) -2 -phenylethylamine hydrochloride By a--method similar to that describedin Example-1'; m-hydroxybenzalmethy1aminewas pre-' It was insoluble. in bene E20; Q.- C- r A solution of 19 g. of m-hydroxybenzalmethyldisso'lyedfin tripleedistilled water to make an analgesic composition of the desired concentratrm uitable in. aimimstmtion.

EXAMPLE 3 A tg g hgdroqzyethyl) -1 (st-methoxyphenyl) -2- phenylethylamine hydrochloride core A mixtureof 68 g of anisicald ehyde, 34 g. of ethanolami'ne and 200 ml. o f'benzlene was igorously shaken for'one hour andthe water liberated in the reaction was removed by drying over anhydrous potassium carbonate. The- Qf anic solution was distilled and theifraction boiling at 106-109 C. at about0.03-mni;, freezing 'point35' C.', was collected.

To a solutionof; benzyl magnesium chloride prepared from 19.5 g. ofma gnesium', 921ml. of benzyl chloride and 300 mli of dry ether was 'added'a; solution of'32.6 g. o ffthe above inter? mediate m' m1. of dryether: fter refluxin for one hour the mixture "was: treated with ice water-and hydrochloric acid.- "The-aqueous 'layer a p r t fidwi hth and made strongly basic with sodium hydroxide. The aqueous; suspension of -ma-gnesiuni hydroxide was extracted repeatedly [with eith ranfdtl e' other solution was washed' with wz jiter''and dried oyerpot'a'ssium carbonate. The'f 'ethefisgjlutiorr was distilled and thecolorless'amine; BQP. CI anemia, w s collected, Eng 1.5727; 113, 1.0952. The amine was conyerted' intof'its "hydrochloride by passing a stream of hydrogen chloride gas through a' solutiorrof; it in dry etheri Thehy' drochloride was recrystallized from absolute a1.

cohol. The M. P, was'l5 4 1 55 5f C; This productwa dissolyed'in; tripl-e distilled water to ma an analgesic'composition of'the desired concentratiorij'for administration.

EXAMIBLEA;

N-aZlyZ-1,2-diphenyZethz/Zamine hydrochloride.

To a solution of benz yl magnesium chloride prepared from 19.5 g. of magnesium, 92 ml. of

' benzyl hloride and- 300 ml. of; 'dry ether, was

- amine separated as a white crystalline precipitate product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration for administration.

EXAMPLE N-methyZ-I-(ZJ dimethomyphenyl) Z-phenulethylamine hydrochloride OCH;

OCH:

2,3 dimethoxybenzalmethylamine was prepared from 83.1 g. of 2,3-dirnethoxybenzaldehyde and 18.6 g. of methylamine in 250 ml. of benzene by refluxing the benzene with a continuous water separating device. After removing the solvent in vacuo the product was distilled. The B. P. was 132 C. at 12 mm.

By a similar method to that described in Example 5, 35.8 g. of this product were allowed to react with benzyl magnesium chloride. The hydrochloride was crystallized from the decomposed reaction mixture and was recrystallized from methanol. The M. P. was 104-125 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration for administration.

EXAIWPLE 6 N-methyZ-l-(Z hydrozy 3 methoxyphenyl) Z-phenylethylamz'ne hydrochloride OCH:

2-hydroxy-3-methoxybenzal methylamine was prepared from 83.1 g. of Z-hydroxy-l-methoxybenzaldehyde and 18.69 g. of methylamine by the method described in Example 6. It distilled at 132 C. at 12 mm.

A solution of 20- g. of this in 50 ml. of dry ether was allowed to react with benzyl magnesium chloride (prepared from 12.7 g. of magnesium, 60 ml. orf benzyl chloride, and 200 ml. of dry ether). The reaction mixture was decomposed with ice and hydrochloric acid and an oily layer of the hydrochloride remained insoluble in both the water and ether layers. This was separated and dried in a, vacuum desiccator and then crystallized from a mixture of absolute methanol and absolute ether. The M. P. was 176-179" C. This product was dissolved in triple-distilled Water to make an analgesic composition of the desired concentration.

EXAMPLE? N-methyZ-l (4 methoxyphenyl) 2 phenylethylamine hydrochloride CHa-CHNHCHa-HC1 .gM o vPh l e zy ketone 9 .sa

methyl rormamlde 19.8 g. were heated at ISO-210 C. for six hours in a distillation apparatus. The

mixture was then refluxed six hours with a mix ture of 40 ml. of concentrated HCl and 100 ml. of water. After cooling, the water solution was decanted and made strongly basic with sodium hydroxide. The crude product which separated was distilled at 116-126" C. at 0.05-0.13 mm., n 1.5643.

The hydrochloride was prepared by adding the amine to a solution of HCl in anhydrous alcohol. The amine hydrochloride was precipitated and washed with dry ether. The M. P. was 139-141 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

EXAMPLE 8 N methyl 1 (4-hydroxyphenyl)-2-phenylethyldmine hydrochloride A mixture of 36.7 g. of p-hydroxybenzaldehyde, about 16 g. of methlylamine, and ml. of benzene was shaken vigorously for 1%. hours, and then the solvent was refluxed, using a continuous water separating device. During the refluxing, the p-hydroxybenzal methylamine crystallized, and, after cooling, it was collected, dried, and recrystallized from dioxane; M. P. 177 C.

To a solution of benzyl magnesium chloride prepared from 19.5 g. of magnesium, 92 ml. of benzyl chloride and 300 ml. of dry ether, was slowly added a solution of 27 g. of the above phydroxybenzal methylamine in 250 ml. of warm dry dioxane. The mixture 'became very thick and 200 m1. of dry benzene were added to facilitate stirring. After refluxing for two hours with stirring, the mixture was decomposed with ice and hydrochloric acid. The layers were separated and after washing the aqueous layer with ether it was made basic by adding an excess of solid sodium carbonate. The mixture was extracted twice with n-butanol and then with ether and the combined extracts were dried over sodium sulfate. The solvent was distilled in vacuo and the residue was taken up in methanol, treated with decolorizing charcoal, and concentrated. Some 4-hydroxystilbene separated (M. P. 186- 187 C.) which was discarded. The filtrate was saturated with hydrogen chloride gas and then diluted with ether to turbidity. After standing, the solution was filtered from a small amount of crystalline precipitate of unkown composition and poured into .water. The aqueous solution was washed with ether and distilled in vacuo to a small volume which crystallized in cooling, The crystals were dissolved in methanol, diluted with ether, and cooled in the refrigerator. Crystals of the amine hydrochloride separated and were collected and dried. The M. P. was I'm-173 C. On continued heating at the melting pointof the sample, it crystallized and remelted at 220-224 desired concentration.

1v methyl 11- ,(3,4 methylenedioxy phenyl) 2- phenyle'fhyldmine hydrochloride OCH2 AJHQ( JH-NH- CHs-HOI .A solution of 32.6 gnof pip'eronal methylamine in 50 ml. of ether was allowed to react with benfzyl magnesium chloride by amethod similar to that described in Example 5. After recrystallization from methanol, the hydrochloride melted at 239-242 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration. 7 V

' EXAMPLE '10 N methyl 1-(3,4-dimeth0.ryphenyl) -2-phenylethylamine hydrochloride Veratral methylamine was made from '50 g. of veratraldehyde and an eXceSs of methylamine loy a method similar to that described in Example =6. It distilled at hid-152 C. at 11 mm.

'By a method similar to that described :in EX- ample 3, 35.8 g. of veratral methylamine was allowed toreact with benzyl magnesium chloride. The amine hydrochloride was recrystallized from a mixture of methanol and ether. The M. P. was

. 154-156 C. This product was dissolved in tri- 'ple-distilled water to make an analgesic .com-

position of the desired concentration.

' EXAMPLE 11 1 (Z-hydroryphenyl) -2-phenyleth- N methyl ylamine hydrochloride ;By a method similar to that decsribed in:Example 7 this amine hydrochloride was made from benzyl magnesium chloride andfi'l g. of salicylal methylamine. After recrystallization from a mixture of absoluteethanol andabsolute ether, the amine hydrochloride melted at 185-189-C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

EXAMPLE ,12

N methyZ- I-(3-ethoscyphenyl) 2 phenylethyle amine hydrochloride .By a method similar to that described 'in Example 6, m-ethoxybenzal methylamine was prepared from 30 g. of m-ethoxybenzaldehyde and ether). from the decomposed reaction mixture'as an -.oil

10 g. T of methylamine. TheB. P.' was.1-22C. at

N-methyl-i (z-methomyphenyl) -2-phenylethylamine hydrochloride By a method similar to that described in Example '7, 25.4 giof o-methoxybenzal methylamine were allowed to react with benzyl magnesium chloride (prepared froml66 g. 0f magnesium, 79 "ml. of "benzyl chloride, and 275 ml. of dry The amine hydrochloride separated which was separated and dried in a vacuum desiccator. It was crystallized from anhydrous acetonefM. P. 123-125 C. This product'was dissolved in triple-distilled water to make an analgesic composition-of the desired concentration.

EXAMPLE .14:

phenJl) ethylamine ydrochloride 0118c com A mixture of 132 g. of desoxyanisoin, 11-8 g.of methyl formamide and '1 m1. of acetic acid was heated at 180-205 o. for twenty-eight hours. The mixture was cooled, washed with water, and the organic layer was boiled for six hours with a mixture of 2 00 m1. of concentrated hydrochloric acid and. 500 ml. of water. After cooling, the aqueous layer was made strongly alkaline with sodium hydroxide. The resulting crude product g.) melted at 56-58? C. and without purification was converted into its hydrochloride and crystallized from acetone with a yield of 7.1 g. The M. P. was 156-1-'59 C. This product wasdissolved in triple-distilled water to make an anal- ;gesiccomposition of the desired concentration.

' Ina-ny'of the amines described, one or more of the hydrogens on the --phenyl -groups can be replaced by an alkyl radical.

EXAMPLE 15 N -B- y 0r thy -1-; edi-r-merhor-yohenyb' ethylamirle hydrochloride o 0 H3 0 o m s I tsmc irmnomomomnoi Desoxyanisoin 30 g, ethanclanii-ne t8 '=g.),

acetic acid (0.2 g.), and benzene (200 ml.) were refluxed using a continuous water separator until no more water was liberated (about six hours). The benzene was then removed under reduced pressure and replaced with absolute alcohol (140 ml.). Sodium metal (12 g.) was added rapidly to the boiling alcohol solution through a reflux condenser. When the sodium had dissolved the alcohol was removed and. the residue was washed with water. The resulting crude N-p-hydroxyethyl ,2 di-p-methoxyphenylethylamine was taken up into dilute hydrochloride acid and washed with benzene. The solution was made strongly basic with sodium hydroxide and extracted with ether. The ether layer was evaporated to dryness, finally under high vacuum, and the residue was converted to its hydrochloride in absolute alcohol. The hydrochloride melted at 210 C. This product was dissolved in triple-distilled water to make an analgesic composition of the desired concentration.

Analgesic compositions of other types than the solution described above may be prepared. Tablets, capsules, ampules or powders, for example, may be made in the usual way employing the customary diluents, extenders, solvents, containers and the like, together with the amines described above. Such analgesic compositions may include more than one of the amines if desired, and the concentration of the amine or amines may be varied to vary the analgesic effect.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above 10 processes and products without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

This application is a division of our copending U. S. Patent application S. N. 592,373, filed August 22, 1946.

We claim:

N-( 2-hydroxyethy1)-1,2-bis(4 methoxyphenyl) -ethylamine.

LOUIS H. GOODSON. ROBERT B. MOFFETT.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,989,325 Lommel et a1. Jan. 29, 1935 2,006,114 Rosenmun'd et a1. June 25, 1935 2,045,574 Adkins et al June 30, 1936 2,276,587 Mettler et a1. Mar. 17, 1942 OTHER REFERENCES Ingersoll et al.: J. Am. Chem. Soc., vol. 58, 

